Nonmetastatic Differentiated Thyroid Cancer Research Articles

Log odds of negative lymph nodes/T stage ratio (LONT): A new prognostic tool for differentiated thyroid cancer without metastases in patients aged 55 and older.

The optimal approach to assess the postoperative status of lymph nodes in differentiated thyroid cancer (DTC) remains controversial. Our aim was to determine if the log odds of negative lymph nodes/T stage ratio (LONT) could serve as a new prognostic and predictive tool for DTC without metastases in patients aged ≥ 55 years. The Surveillance, Epidemiology, and End Results (SEER) database was used to study the role of LONT in patients aged ≥55 years diagnosed with DTC without metastases. The primary outcome was overall survival (OS). The Kaplan-Meier method and the Cox proportional hazard regression model were used to calculate the outcome. Moreover, the robustness of research findings was evaluated using sensitivity analyses. A total of 21,172 DTC patients aged ≥55 years without distant metastasis were enrolled. Multivariate Cox regression analyses and a "floating absolute risk" analysis showed that a LONT ≥0.920 (vs. -0.56 to 0.92) was a protective factor for OS in DTC patients. Sensitivity analyses revealed an E-value of 1.98 for the obtained LONT value. In subgroup analyses, LONT was correlated significantly with OS in different subgroups of negative lymph nodes, stage-I-II subgroups and the N0 subgroup. The conditional probability of survival of DTC improved with prolonged survival time in the LONT ≥0.920 group. A high LONT was associated with longer OS compared with low LONT in patients aged ≥55 years with non-metastatic DTC. LONT could provide valuable information for undertaking postoperative evaluations.

MON-559 Inappropriate Dosing of I-131 in Non-Metastatic Differentiated Thyroid Cancer

Differentiated thyroid cancer (DTC) accounts for the majority of thyroid cancers. While radioactive iodine (RAI) treatment after thyroidectomy plays an adjunctive role in some patients, the majority of patients with DTC at our institution receive RAI. The dosing of RAI is mostly empiric. A low dose of 30 mCi of I-131 is generally favored over higher doses in low or intermediate risk disease with lower risk features while higher doses may need to be considered for high risk patients (Haugen et al.). Higher rates of nausea, neck pain, lacrimal and salivary gland dysfunction and altered taste have been described for 100 mCi of I-131 compared with 30 mCi (Schlumberger et al. and Mallick et al.). The aim of this study was to determine the average dose of RAI for DTC and to identify the risk factors in low risk patients who received high dose of 131-I (≥100 mCi) at our tertiary care institution. Methods: This was a retrospective study of 33 patients with DTC who underwent RAI treatment from January 2015-May 2018 at a single academic medical center. Data were collected from the Nuclear Medicine department. Patients over the age of 18 with a documented non-metastatic DTC diagnosis were included. Patients who received RAI at an outside facility or with no pathology report were excluded. Results: Post-operative ultrasound was not routinely performed, and only 30% of patients had a neck US before RAI dose administration. The average dose of I-131 was 75.7 mCi regardless of the American Thyroid Association (ATA) risk. Sub-analysis per ATA risk group for the average dose showed 64.7 mCi in the low risk group, 98.9 mCi in the intermediate risk group, and 95.9 mCi in the high-risk group. The tertile ranges for the RAI dose were: T1: 29-33, T2:79-115 and T3:150 mCi. 63% of patients in the low risk group received a low dose of I-131(29-33m Ci), 22 % received 79-115 mCi and 13 % received 150 mCi. In the intermediate risk group 28% received 29-33 mCi and 28% received high dose 150 mCi while 42% received 79-115 mCi. In the high-risk ATA group 25% received a low dose of I-131with 29-33 mCi. Patients in the low risk group who received more than 30 mCi but less than 150 mCi showed no high-risk features with undetectable Tg level and no high risk histopathologic features or significant lymphadenopathy. However, of the patients in the low risk group who received ≥150 mCi, 75% had an elevated stimulated Tg level > 10 ng/ml and only one patient had a post-operative neck ultrasound that showed residual tissue. Conclusion: In this small cohort, patients with non-metastatic DTC received intermediate to high doses of RAI regardless of the ATA risk. More than 1/3 of patients in the low risk group received more than the recommended RAI dose per ATA guidelines. Despite the obvious multiple benefits of RAI post-operatively, selective criteria should be used to avoid unnecessary exposure of high dose RAI that may carry additional risk both in the short and long term.

Short Call Abstracts

Short Call Abstracts

Extrathyroidal Extension: Does Strap Muscle Invasion Alone Influence Recurrence and Survival in Patients with Differentiated Thyroid Cancer?

According to the 8th edition American Joint Committee on Cancer staging system, extrathyroidal extension (ETE) and primary tumor size remain the principle determinants of T stage. However, impact of gross ETE into strap muscles on survival remains controversial. A retrospective review of 2084 patients with ≤ 4cm nonmetastatic differentiated thyroid cancer who underwent surgery between 2000 and 2015 was conducted. Patients were divided into three groups according to degree of ETE: no ETE (group 1), ETE into perithyroidal soft tissue (group 2), and gross ETE into strap muscle (group 3). Survivals were analyzed using Kaplan-Meier method and compared using log-rank test. Factors predictive of survival were analyzed using Cox proportional hazard model. Ten-year disease-free survival (DFS) of patients in groups 1-3 was 90, 82, and 83%, respectively (p = 0.003). On multivariate analysis, age ≥ 55years, male sex, and pathologic N1b category predicted significantly worse DFS, while ETE into perithyroidal soft tissue or gross strap muscle invasion did not predict worse DFS. Overall survival (p = 0.957) and disease-specific survival (p =0.910) were not significantly different between the three groups. There was a statistically significant difference in locoregional recurrence-free survival between groups 1 and 2 [HR 2.02, 95% CI 1.06-3.94]. Gross strap muscle invasion may not be an important survival prognostic factor for staging purposes. Although both gross strap muscle invasion and perithyroidal soft tissue extension may be predictive for locoregional recurrence, the distinction between them may not be as important for postoperative risk stratification.

Suppressed thyroglobulin performs better than stimulated thyroglobulin in defining an excellent response in patients with differentiated thyroid cancer.

According to the American Thyroid Association guidelines in 2015, both an unstimulated thyroglobulin (u-Tg) below 0.2 ng/ml and a stimulated thyroglobulin (s-Tg) below 1.0 ng/ml were required along with negative imaging findings to define an excellent response. This study aimed to investigate whether a u-Tg below 0.2 ng/ml coincides with a s-Tg below 1 ng/ml. A total of 290 patients with nonmetastatic differentiated thyroid cancer were retrospectively evaluated with a median follow-up of 36 months. The levels of s-Tg were observed in patients whose u-Tg levels were below 0.2 ng/ml after radioiodine therapy, and risk factors associated with the increase of s-Tg to above 1 ng/ml from below 0.2 ng/ml were analyzed. In total, 52.8% (153/290) of the patients achieved a u-Tg below 0.2 ng/ml 3 months after remnant ablation, most of whom (83.7%, 128/153) also achieved a s-Tg below 1 ng/ml. A total of 25 (16.3%) patients had an increased s-Tg above 1 ng/ml. A comparative analysis showed no significant difference between patients who showed an increase in thyroglobulin from below 0.2 ng/ml to above 1 ng/ml and those who did not. In a subgroup analysis assessing the influence of thyrotropin (thyroxin-stimulating hormone) on s-Tg, we enrolled 43 patients with at least two s-Tg measurements. We found that a higher level of thyroxin-stimulating hormone (118.23±30.72 vs. 59.99±26.12 µIU/ml) increased the s-Tg in 88.4% patients (P=0.00), which led to more patients (18.6-30.2%) with an increased s-Tg (to above 1 ng/ml) after thyroxin withdrawal. Assessment of the level of u-Tg might be a better parameter to use for defining excellent response as u-Tg is more stable, convenient, economical, and is not associated with hypothyroidism as a side effect.

Refining Dynamic Risk Stratification and Prognostic Groups for Differentiated Thyroid Cancer With TERT Promoter Mutations.

Currently, no recurrence or mortality risk systems consider molecular testing when predicting thyroid cancer outcomes. We developed an integrative prognostic system that incorporates telomerase reverse transcription (TERT) promoter mutations into the recently proposed risk reclassification system after initial therapy [dynamic risk stratification (DRS)] to better categorize and predict outcomes. A total of 357 differentiated thyroid cancer (DTC) patients without initial distant metastasis were enrolled. Among patients with mutated TERT and wild-type, recurrence-free survival (RFS) was compared according to DRS grouping. Cox regression was used to calculate adjusted hazard ratios (AHRs) to derive AHR groups. Performance of the AHR grouping system with respect to prediction of structural recurrence and cancer-specific survival (CSS) was assessed against the current DRS system and the tumor/node/metastasis (TNM) classification. Among 357 patients, there were 90 recurrences and 15 cancer-related deaths during a median of 14 years of follow-up. Patients in higher AHR groups were at higher risk of recurrence (10-year RFS for AHR 1, 2, 3, and 4: 94.9%, 82.7%, 50.2%, and 23.1%; P < 0.001) and cancer-related death (10-year CSS: 100.0%. 98.7%, 94.2%, and 76.9%; P < 0.001). The proportions of variance explained (PVEs) for the ability of AHR and DRS grouping to predict recurrence were 22.4% and 18.5%. PVEs of AHR and TNM system to predict cancer-related deaths were 11.5% and 7.4%. The AHR grouping system, a simple two-dimensional prognostic system, is as effective as DRS at predicting structural recurrence and provides clinical implication for long-term CSS in patients with nonmetastatic DTC.

Impact of neck failure on survival in older patients with differentiated thyroid cancer.

Regional recurrence of differentiated thyroid cancer (DTC) is often salvaged with neck dissection without survival penalty. It is unknown whether recurrence may be associated with inferior survival in older patients. Surveillance, Epidemiology, and End Results (SEER) and Medicare data were linked to identify patients age ≥65 with nonmetastatic DTC. Patients undergoing neck dissection >6 months after their initial diagnosis were considered to have regional recurrent disease. We compared overall survival (OS) and cause-specific survival (CSS) for patients with recurrent disease versus a matched cohort of patients with non-recurrent DTC. Of 6235 patients, 143 had treatment-defined recurrent disease. Patients with recurrent disease had inferior OS (p < .01) and CSS (p < .01). Multivariate analysis demonstrated that recurrent disease was independently associated with inferior 10-year OS (hazard ratio [HR] = 1.75; p < .01) and CSS (HR = 3.05; p < .01). Regional recurrence of DTC may negatively impact OS and CSS in patients ≥65 years old. © 2016 Wiley Periodicals, Inc. Head Neck 38: 919-924, 2016.

Response to (131)I Therapy in Non-metastatic Differentiated Thyroid CancerPatients with Preablative Stimulated Thyroglobulin above 10 ng/ml.

To evaluate the response of (131)I therapy and to explore the influencing factors in non-metastatic differentiated thyroid cancer (DTC) patients with preablative stimulated thyroglobulin (ps-Tg) above 10 ng/ml. The study included 157 DTC patients who had undergone total or near total thyroidectomy and subsequent (131)I therapy with ps-Tg>10 ng/ml, and they were divided into 3 groups as excellent response (ER, 49 cases), acceptable response (AR, 36 cases), and incomplete response (IR, 72 cases) according to the response to (131)I therapy. We compared the clinicopathologic features and ps-Tg levels among 3 groups, as well as ps-Tg levels between IR and non-IR groups. The ROC curve was employed to evaluate the predictive value of ps-Tg levels in (131)I therapy responses. The three groups showed significant difference in ps-Tg levels (H=35.142, P<0.001), gender (χ(2)=6.82, P=0.033), extrathyroid invasion (H=31.380, P<0.001), and lymph metastases (H=14.375, P=0.001). The ps-Tg level in IR is higher than that in non-IR (U=1384.5, P<0.001), while it was not significantly different between ER and AR (U=771.5, P=0.326). The diagnostic critical point (DCP) of ps-Tg to differentiate IR and non-IR was 28.3 ng/ml (sensitivity 57.5%, specificity 87.1%), with a corresponding area under the ROC curve (AUC) of 0.774 (95%CI: 0.701-0.847). Near-half (45.86%) non-metastatic DTC patients with ps-Tg above 10 ng/ml are more susceptible to IR. The level of ps-Tg>28.3 ng/ml may be a useful and sensitive diagnostic marker for predicting incomplete response.

Low-dose radioiodine ablation in differentiated thyroid cancer with macroscopic extrathyroidal extension and low level of preablative-stimulated thyroglobulin.

High-dose radioactive iodine (RAI) is recommended for patients with nonmetastatic differentiated thyroid cancer with macroscopic extrathyroidal extension (MAEE). It is unclear whether these patients can be treated with low-dose RAI when preablative-stimulated thyroglobulin (ps-Tg) is low. This randomized study aims to evaluate the clinical outcome and ablative efficacy of low-dose radioiodine in patients with MAEE but with low ps-Tg level. Differentiated thyroid cancer patients with complete thyroidal resection, MAEE, any N stage, ps-Tg less than or equal to 5 ng/ml when thyroglobulin antibodies are less than or equal to 46 IU/ml, and no evidence of distant metastasis were included in the study. Patients were randomly allocated to receive low-dose (1110 MBq) or high-dose RAI (3700 MBq). Follow-up was generally performed 6 months after ablation. Successful ablation was identified as (i) stimulated thyroglobulin 1.0 ng/ml or less when thyroglobulin antibodies 46 IU/ml or less; (ii) negative Dx-WBS; and (iii) negative neck ultrasonography. Clinical recurrence was defined as the reappearance of disease confirmed by cytology or pathology. A total of 102 patients were analyzed: 51 in the low-dose group and 51 in the high-dose group. There was no significant difference in clinicopathological characters between the two groups. No patient had clinical recurrences during the mean 6.8 months of follow-up. Ablation was successful in 43 of 51 (84.3%) patients in the low-dose group and in 44 of 51 (86.27%) patients in the high-dose group, and thus no significant difference was noted (P=0.7798). Ablation with low-dose RAI has been proven to be noninferior to high-dose RAI in nonmetastatic patients with MAEE when ps-Tg level is less than 5 ng/ml.

The Efficacy of Thyrotropin Suppression Therapy in Treatment of Differentiated Thyroid Cancer after Total Thyroidectomy

Abstract Background: The aim of this prospective study was to assess the effect of the TSH suppression on both disease-free and overall survivals in patients with nonmetastatic differentiated thyroid cancer (DTC) after total thyroidectomy. Patients &amp; Methods: One hundred and forty eight patients with pathologically proved operable differentiated thyroid carcinoma were enrolled in this prospective study. Levothyroxin (L-T4) therapy was started in doses according to treatment groups. Patients were randomly assigned to receive either postoperative TSH suppression therapy in group I (76 patients) or nonsuppression therapy in group II (72 patients). Results: During the period of follow up with a median 54 months, the disease-free survival for patients without TSH suppression therapy did not reach statistically significant difference comparing with those for patients with the suppression therapy (p=0.09). However, the difference was statistically significant for high-risk patients (p=0.04). On comparing both groups there was no statistically significant difference with regard to overall survival (p=0.17). The age of the patients more than 45 years, tumour size more than 4 cm and high-risk group were significant independent predictors for thyroid carcinoma-related relapse in univariate analysis. However, tumour size was the only significant factor in multivariate analysis. Conclusion: Suppressive treatment with L-T4 therapy in patients with differentiated thyroid carcinoma should be individualised and balanced against the adverse effects. TSH suppression is indicated in patients with high-risk disease or recurrent tumour. Normalisation of serum TSH is preferred for long-term treatment of disease-free elderly patients with DTC and comorbidities.

Quality of life in patients with non-metastatic differentiated thyroid cancer under thyroxine supplementation therapy.

When thyroid and other cancers are "cured" it is often assumed that the patients are able to resume their normal lives. This was a cross-sectional study to evaluate health-related quality of life (HRQOL) and to identify rehabilitation needs of patients with non-metastatic thyroid cancer under thyroxine supplementation therapy. Included in the study were 150 consecutive patients with differentiated thyroid cancer (age 52 +/- 14 years, range 25-83 years; male/female 39/111). All patients had a history of total thyroidectomy followed by radioiodine ablation, were free of metastatic disease and under levothyroxine treatment. The mean period since the diagnosis of thyroid cancer was 5.5 +/- 6 years (range 0-23 years). Health-related quality of life was evaluated using the SF-36 Health Survey. The findings were compared with sex- and age-matched reference values. "Role-emotional" and "Vitality" were significantly lower ( P<0.001 and P<0.005, respectively) in the group as a whole ( n = 150). In the subgroup of patients with a recent (less than 1 year) diagnosis of thyroid cancer ( n = 51), however, the following subscales were significantly lower: "Mental Health" ( P<0.01), "Role-emotional" ( P<0.001), "Role-physical" ( P<0.005), "Social functioning" ( P<0.005) and "Vitality" ( P<0.001). Multiple regression analysis identified a significant positive correlation between "Mental Health", "Physical functioning", "Vitality", "Role-emotional" and "Social functioning" with the time since initial diagnosis, and there was also a positive correlation between "Physical functioning", "Bodily pain" and "Role-emotional" with male gender. These findings indicate that "Vitality", "Role-physical", "Mental Health", "Role-emotional" and "Social functioning" are significantly impaired during the first year after diagnosis. Thereafter, quality of life improves correlating with the time since initial diagnosis. However, "Vitality" and "Role-emotional" remain permanently impaired in thyroid cancer patients. A multidisciplinary rehabilitation concept should include psychological support and an early start to exercise to improve physical performance of these patients leading to better HRQOL and to help them fulfill their social role earlier.

Serum levels of carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in the differential diagnosis of the syndromes of inappropriate secretion of TSH.

Serum TSH assay is a very sensitive and specific index of thyroid hormone (TH) action. Nevertheless, in particular clinical situations, such as those of inappropriate TSH secretion, the measurement of additional parameters evaluating peripheral TH action may be required in order to achieve a correct diagnosis and to assess the impact that thyroid hormone have on a given tissue. The availability of a specific RIA for serum carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) prompted us to study the usefulness of this specific marker of bone resorption in the differential diagnosis of thyroid disorders. Serum ICTP levels were measured in: (a) 10 patients with TSH-secreting pituitary adenoma (TSH-oma), (b) 40 with thyroid hormone resistance (RTH), as well as in (c) 28 patients with Graves' disease or toxic nodular goitre, (d) 31 with autoimmune primary hypothyroidism (PH) and in 8 of them during L-T4 replacement therapy, (e) 23 with central hypothyroidism (CH) during L-T4 therapy and 2 months after its withdrawal, and (f) 26 during TSH-suppressive treatment for goitre or non-metastatic differentiated thyroid cancer. Results were compared with those obtained in 2 groups of normal controls (Group A, n = 61, age range: 23-68 years; Group B, n = 32, age range: 6-15 years). Serum TSH, free T4 (FT4) and free T3 (FT3) were measured by immunofluorometric assays. Serum ICTP was measured by a specific RIA with a sensitivity of 0.5 +/- 0.1 microgram/l, and intra- and interassay coefficients of variation lower than 6%. Mean values of serum ICTP levels in adult controls were 3.8 +/- 1.6 (+/-SD) microgram/l, while in pre- or peri-pubertal controls it was higher than in adults (14.4 +/- 3.1 micrograms/l). Patients with TSH-oma showed significantly increased ICTP levels (8.7 +/- 5.0 micrograms/l, P < 0.001 vs controls), in contrast to those with RTH (3.0 +/- 1.0 micrograms/l, P < 0.02 vs controls). In the differential diagnosis of inappropriate secretion of TSH, ICTP values above 5 micrograms/l strongly indicated the presence of a TSH-oma. Circulating ICTP concentrations were definitely high in thyrotoxic patients (9.4 +/- 4.7 micrograms/l, P < 0.001) and values overlapping the normal range were observed in 8 cases, thus giving to this test a sensitivity and specificity of 71% and 93%, respectively. In contrast, serum ICTP levels in both PH and CH untreated patients were in the normal range, although significantly lower than in controls (2.6 +/- 1.0 and 1.8 +/- 0.7 micrograms/l, P < 0.001). During replacement therapy, ICTP levels rose significantly in both hypothyroid groups (5.1 +/- 2.5 and 2.7 +/- 1.3 micrograms/l). In 2 CH patients, borderline high ICTP levels (7.0 and 7.1 micrograms/l), associated with FT3 concentrations in the upper limit of the normal range, suggested the presence of L-T4 overtreatment; L-T4 dose reduction was followed by the decrease of both indices in a more physiological range (ICTP: 4.2 and 4.7 micrograms/l; FT3: 8.5 and 6.0 pmol/l). In patients treated with TSH-suppressive therapy at the minimal effective dose, ICTP levels did not significantly differ from those observed in adult controls (4.3 +/- 2.0 micrograms/l). The overall correlations between serum ICTP and FT4 or FT3 levels were highly significant (P < 0.001). The present data indicate that serum type I collagen (ICTP) concentrations are modulated by circulating thyroid hormone concentrations. ICTP measurement is particularly useful in the differential diagnosis of the syndromes of inappropriate TSH secretion, in estimating thyroid hormone impact on bone in primary hyperthyroid states, and its longitudinal evaluation may reveal L-T4 overtreatment in patients on substitutive or TSH-suppressive therapy.